The invention relates to stents with a radioactive surface coating, processes for their production and their use for restenosis prophylaxis.
Radioactive stents are prior art (EP 0433011, WO 94/26205, U.S. Pat. No. 5,176,617). Stents are endoprostheses that make it possible to keep open duct-like structures in the bodies of humans or animals (e.g., vascular, esophageal, tracheal and bile duct stents). They are used as palliative measures in the case of stenoses by obstruction (e.g., arteriosclerosis) or external pressure (e.g., in the case of tumors). Radioactive stents are used, for example, after vascular-surgery interventions or radiological interventions (e.g., balloon angioplasty) for restenosis prophylaxis. Such radioactive stents can be produced, for example, by activation of a non-radioactive stent using irradiation with protons or deuterons from a cyclotron (WO 94/26205). This process for the production of radioactive stents is named ion implantation.
There is now the problem that, on the one hand, generally no cyclotron is available at the site of the use of the stent to undertake an activation of the stent, and, on the other hand, the activated stent cannot be stored indefinitely or transported in any arbitrary way due to the sometimes short half-life of the activated isotope and for reasons of protection against radiation.
The object of this invention is therefore to make available stents and new processes for their production, and said stents can be activated independently by a cyclotron. In particular, the object of the invention is to make available stents that can be coated independently by a cyclotron with a preselected radioactive isotope.
This object is achieved by the stents that are described below and the processes for their production, as they are characterized in the claims.
The above-described object is achieved by the production processes for radioactive stents that are described below. In contrast to ion implantation, the processes according to the invention for the production of radioactive stents are based on chemical or electrochemical methods.
Within the framework of this application, the notations nnX and X-nn (X: element symbol, nn: mass number) are to be regarded as synonymous for radioactive isotopes (Example: 110Ag corresponds to Ag-110).
The above-described object is achieved in a first variant by a process for the production of a radioactive stent, in which a chemical deposition of the radioactive isotope is carried out on the stent.
To this end, the selected stent is immersed in a solution that contains the radioactive isotope. The radioactive isotope is then chemically deposited on the stent. Depending on the selected material of the stent, on the one hand, and the radioactive isotope that is to be deposited, on the other hand, two possible types of deposition are considered:
1) Chemical Reduction
During chemical reduction, a reducing agent (e.g., SnCl2, KBH4, dimethylborane, formaldehyde, sodium hypophosphite) is added to the solution that contains the radioactive isotope in dissolved form as well as the stent.
Survey:
M2++2exe2x88x92(from the reducing agent)xe2x86x92catalytic surfacexe2x86x92M0
Reducing agent hypophospbite (with Ni)
H2PO2xe2x88x92H2Oxe2x86x92catalytic surfacexe2x86x92HPO32xe2x88x92+2H++Hxe2x88x92
2Hxe2x88x92+Ni2+xe2x86x92Ni H2
Addition of citrate, acetate, fluoride, succinate, lactate, propionate
pH=4xe2x88x9211 
Reducing agent NaBH4 (with Au, Ni)
BH4xe2x88x92+H2Oxe2x86x92BH3OHxe2x88x92+H2
BH3OHxe2x88x92+3Au(CN)2xe2x88x92+3OHxe2x88x92xe2x86x92catalytic surfacexe2x86x92BO2xe2x88x92+1.5H2+3Au0+6CNxe2x88x92+2H2O
xe2x80x832Ni2++NaBH4+2H2Oxe2x86x92catalytic surfacexe2x86x922Ni0+2H2+4H++NaBO2
Additions of dimethylammonium borane, boric acid, citric acid, malonic acid, glycine, pyrophosphate, malic acid,
pH=4-10
Reducing agent formaldehyde: (with Cu)
Cu2++2HCOH+4OHxe2x88x92xe2x86x92catalytic surfacexe2x86x92Cu0+H2+2H2O+2HCOOxe2x88x92
with the addition of NaKtartrate, NaOH
Reducing agent hydrazine: (with Pd, Pt)
Pd, Pt with the addition of NH4OH, EDTA,
Reducing agent dimethylaminoborane (CH3)2NHxe2x80x94BH3 (with Au, Ag)
(CH3)2NHxe2x80x94BH3+OH-xe2x86x92catalytic surfacexe2x86x92BH3OHxe2x88x92+(CH3)2NH
Au and Ag from cyanidic baths
After 1 minute to 10 hours, the stent is removed from the respective solution and washed. The stent is coated on the surface with the radioactive isotope.
In this way, for example, radioisotopes of elements Ag, Au, Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, P, Pb, Pd, Pm, Pt, Re, Rh, Ru, Sc, Sm, Tb, Tc or Y can be deposited on metal stents (e.g., steel, nitinol).
2) Chemical Precipitation
During chemical precipitation, a precipitating agent (e.g., oxalic acid, phosphoric acid or salts thereof or Na2CO3) is added to the solution that contains the radioactive isotope in dissolved form as well as the stent.
In this way, for example, radioisotopes of elements Ag, Au, Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, Pb, Pd, Pm, Pt, Re, Rh, Ru, Sc, Sm, Tb, Tc or Y can be deposited on metal stents (e.g., steel, nitinol).
The above-described object is achieved in a second variant, in that the radioactive isotope is secured by means of an adhesive to the surface of the stent.
The device according to the invention thus consists of the metal parent substance of the stent, an adhesive on the surface of the stent and an adhesive radioactive isotope.
As a parent substance, the commercially available vascular implants can be used, e.g., a Wiktor stent, a Strecker stent or a Palmaz-Schatz stent.
As adhesives, peptides, fats or gold in combination with a thiol-group-containing complexing agent are used.
It is thus possible, for example, to use modified polyurethanes that in turn contain complexing agents.
As adhesives, however, peptides can also be used that on the one hand carry a complexing agent and on the other hand bind specifically to the metal of the stent. Examples of these compounds ar labeled endothelin derivatives, as they are described in, e.g., EP 606683, DE 4425778, DE 43 37 600, DE 4337599 and DE 19652374 (e.g., Tc-99m-Asp-Gly-Gly-Cys-Gly-Cys-Phe-(Dr-Trp)-Leu-Asp-Ile-Ile-Trp).
As adhesives, fats that carry a complexing agent can also b used. Examples of this are the complexing agents that carry lipophilic radicals and that are mentioned in DE 43 40 809, EP 450742, EP 438206, EP 413405 or WO 96/26182.
Moreover, gold in combination with a thiol-group-containing complexing agent can also be used as an adhesive. It is known that thiol-group-containing compounds show an increased affinity to gold-coated surfaces (H. Schxc3x6nherr et al. J. Am. Chem. Soc. 118 (1996), 13051-13057). Surprisingly enough, elementary gold that is on the surface of the stent is also able to secure specific complexing agents, if they have thiol groups. The complexing agents in turn secure the radioactive isotopes.
For the purposes of this document, complexing agents are, e.g., DTPA, DOTA, DO3A, EDTA, TTHA, MAG2-amides, MAG3-amides and derivatives thereof.
As radioactive isotopes, the radioactive isotopes of elements Ag, Au, Ba, Bi, C, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, P, Pb, Pd, Pm, Pt, Re, Rh, Ru, S, Sb, Sc, Sm, Tb, Tc or Y can be used.
The invention therefore relates to radioactive stents, characterized in that the radioactive isotope is secured to the surface of the stent by means of an adhesive.
The stents according to the invention can be produced as follows by way of example:
A. Peptide as an adhesive
A.1 First, a peptide is selected that for its part is able to complex heavy metal ions. The latter is activated by reaction with the radioactive isotope (e.g., 186Re or 188Re) optionally together with a reducing agent. The radiolabled peptide is dissolved in a solvent (e.g., water, phosphate buffer), and the stent is immersed in the peptide solution. After the stent is removed from the peptide solution, it is dried in a drying chamber at room temperature. After the stent is washed, the latter is ready for use.
A.2 In a variant of the process, the uncoated stent is first coated with the non-activated peptide. The thus coated stent is then immersed in a solution that contains the radioactive metal (e.g., 186Re or 188Re) optionally together with a reducing agent (e.g., SnCl2) and thus is charged with this isotope. After the stent is washed, the latter is ready for use.
B. Fat as an adhesive
B.1 An uncoated stent is first coated with a lipophilic compound (e.g., 3,9-bis(carboxymethyl)-6-bis(octadecyl)-aminocarbonylmethyl-3,6,9-triazaundecanedioic acid, WO 96/26182) as an adhesive. This lipophilic compound carries a DTPA radical as a complexing agent. The stent can be directly immersed in the compound or a solution thereof. After the stent is coated with the compound, it is mixed with a solution of the radioactive metal (e.g. 90YCl3). After the stent is washed, the latter is ready for use.
B.2 In a variant of this process, the coating of the stent is carried out in two stages. In this regard, the stent is first treated with a lipophilic compound that carries amino groups. The amino groups are then reacted with DTPA-monoanhydride, as it is described in the literature. The stent now has a coating that carries the complexing agents (here: DTPA). The stent that is coated in this way is then mixed with a solution of radioactive metal (e.g. 90YCl3). After the stent is washed, the latter is ready for use.
C. Gold/thiol-group-containing complexing agents as adhesives
C.1. An uncoated stent is first coated electrochemically with elementary gold (by internal electrolysis, cementation). The gold-coated stent is then immersed in an aqueous solution of a thiol-group-containing complexing agent (e.g., N,N-dimethyl-2-(3,3,5,11,13,13-hexamethyl-1,2-dithia-5,8,11-triazacyclotridecan-8-yl)-ethylamine or the coupling product of 11-amino-undecyl-1-thiol with DTPA-bis-anhydride). The thiol-group-containing complexing agent adheres to the gold-coated stent. The stent that is prepared in such a way is now mixed with a solution of the radioactive metal (e.g., 67CuSO4). After the stent is washed, the latter is ready for use.
xe2x80x83The complexing agent can be synthesized on the surface of the stent. It is possible to apply first only one component of the complexing agent to the gold-coated stent and then to couple this component with additional partial units. This procedure is described in detail in the examples.
C.2 In a variant of this process, the gold-coated stent is mixed with a solution of the thiol-group-containing complexing agent, which for its part already complexes a radioactive isotope. After the stent is washed, the latter is ready for use.
C.3 In a variant of this process, the gold-coated stent is mixed with a solution of the thiol-group-containing compound, which in turn contains 35S. After the stent is washed, the latter is ready for use.
C.4 In another variant of this process, the gold-coated stent is mixed with a solution of the thiol-group-containing complexing agent, whereby the thiol group is labeled with 35S, and the complexing agent already complexes a radioactive isotope (e.g., 67Cu). After the stent is washed, the latter is ready for use.
The above-described processes are generally performed at temperatures of 0-100xc2x0 C. In the coating of the stent with the adhesive, solvents can be used on the basis of the respective adhesive. When a non-aqueous solvent is used, the latter is to be removed before the implantation.
The stents can also be coated with two or more different isotopes. It is possible in particular to apply short-lived or long-lived isotopes together on a stent (for example, 55Co with 55Fe, 35S with 67Cu or 99Mo with 57Co).
The operations that are necessary for implementing the above process that is described in principle are known to one skilled in the art. Special embodiments are described in detail in the examples.
In a third variant, the invention also relates to a process for the production of radioactive stents, which is characterized in that a non-radioactive stent is immersed in a solution that contains at least one radioactive isotope in ionic form, and the isotope is then chemically deposited on the stent.
The above-described object is achieved according to the invention by an electrochemical deposition of the radioactive metal isotope on the stent.
To this end, the selected stent is immersed in a solution that contains the radioactive metal isotope. The radioactive isotope is then electrochemically deposited. On the basis of the selected materials of the stent, on the one hand, and the radioactive isotope that is to be deposited, on the other hand, two possible types of deposition are considered:
I) Electroplating (external electrolysis)
During electroplating, the dissolved radioactive isotope is deposited reductively by applying electrical direct current to the stent that is connected as a cathode.
In this way, for example, copper, technetium, rhenium, silver or indium can be deposited on electrically conducting stents (e.g., steel, nitinol).
II) Cementation (internal electrolysis)
During cementation, the dissolved noble radioactive isotope is deposited on the non-noble stent material without applying electrical current due to the position of the materials in the voltage sequence of the metals. In this way, for example, gold, silver or copper can be deposited on metal stents (e.g., steel, nitinol).
For the coating of metal stents, two electrochemical processes have proven especially suitable: electroplating (electrolytic coating) and cementation (internal electrolysis). The process with the broader range of application is the electroplating, since it also makes possible the coating with an electrochemically more negative material than that of the stent. The coating also makes possible chemical reactionsxe2x80x94for example reductive processes.
From the user-friendly operation, it can be seen that the cementation is the better process: the stent is added to the solution of an electrochemically more positive element, and the coating is carried out without a parasitic current.
By suitable cell shape, the excess coating material can be kept small. The necessary stirring can be done by a magnetic stirrer or by moving the stent manually. Since only small amounts of substance are applied in this process, manual stirring is reasonable. The same also holds true for reactions at elevated temperature: because of the short time available, thermostating is not necessary; preheating is all that is required.
The coating of cells (FIGS. 1, 2) can be carried out with hypodermic syringes orxe2x80x94in the case of larger stentsxe2x80x94with the aid of metering pumps. With these larger cells, it is useful to separate used electrolyte solution (active) and washing liquid (inactive) to keep the volume of active liquid small.
In the cells that are described in FIGS. 1, 2, the stent is placed with its carrier in the vessel, whereby an elevated location with a trough provides for the positioning. In the case of a galvanization cell, this trough contains a Pt sheet as a contact for the stent that is connected as a cathode. A Pt network is located on the cell wall as an anode. By using on of the ring-shaped sheets which is connected in an electrically conducting manner with the anode and that is made of another metal, the operation can also be done with tin, zinc or copper anodes.
The use of the stent with its carrier has the advantage that the inside of the stent is shielded, and thus no coating is carried out there. The coating is carried out only at the locations that are directed against the vessel.
Since a restenosis is suppressed by the coating, an electropolishing of the crude stent may be omittedxe2x80x94especially in the case of high-grade steel.
Possible Types of Electrochemical Labeling of Stents: Galvanostatic Deposition
For this purpose, a battery (1.5-12 V) that is connected with a variable resistor and 2 electrode terminals is sufficient. The metal that is to be coated is connected as a cathode. As an anode, a noble metal, preferably platinum, should be used. The electrolysis period is 20 seconds to 30 minutes. The operation is performed at temperatures of 0xc2x0-80xc2x0 C., but preferably at room temperature.
Cu: (e.g., Cu-67, xcex2 and xcex3 Str., txc2xd=61.9 h)
from pyrophosphate baths of the composition below:
from alkaline CuCN baths at pH 12.2-12.8
from acid baths of
sulfate-oxalate-boric acid
Cucl/Na-thiosulfate
fluoroborate, fluorosilicate, formate
Cu11/gluconate, lactate, maleate, tartrate
I=1-2.5 A/dm2 
U=0.2-6 V
pH=1.2
Au: (Au-199, txc2xd=3, xcex2 and xcex3 Str.)
from cyanidic baths with the addition of phosphate and citrate at pH 5-12,
from baths of NH4ClKAuCN2 with the addition of thiourea at pH 6.5-7
I=0.1-0.6 A/dm2 
In:
from cyanidic baths at pH=0-1
from fluoroborate baths with the addition of tartaric acid at pH 1
In2(SO4)3 pH 2-3/or sulfamate and tartrate
Re: from perrhenate Re-186
citrate+H2SO4, pH 1-5
I=1-15 A/dm2 
Ni:
from NiSO4/boric acid or from acetate, fluoroborate or sulfamate baths,
pH=1-5
I=2-30 A/dm2 
Pt, Rh, Pd, Ru:
(Pt-197, txc2xd=xcex2 Str.)
I=2-4 A/dm2 
Ru from (NH3)4(Ru2NC18(H2O)2) or sulfamate
Rh from the sulfate or phosphate with the addition of H2SO4 
pH=1-2
Pd from Pd(NH3)4Br2, ETDA,
Pt from H2Pt(NO2)2SO4 with the addition of NH4NO2, NH3 sulfamate
H2Pt(NO2)2SO4 with the addition of H2SO4 
K2Pt(OH)6 with the addition of KOH and/or ethylamine
H2PtCl6 in acid baths with the addition of HCl
Ag: (Ag-110, txc2xd=250d)
from cyanidic baths with the addition of KOH
Electrochemical Deposition
The labeling of the stent is done by electrochemical deposition of radioactive metal corresponding to its electrochemical potential in terms of the potential of the stent metal. The deposition is performed in a suitable electrolyte and under selected reaction conditions. An especially suitable electrolyte is hydrochloric acid at the concentrations of 0.75 N and 1 N. In this way, all radioisotopes of metals, whose electrochemical potential is more positive than that of the stent metal, can be deposited.
It has been shown that after the electrochemical deposition of the radioactive metal, nonspecifically-bonded activity still adheres to the stent to some extent. To remove the latter, the stent is treated with a solution that contains an electrolyte (e.g., NaCl), a reducing agent and a hydroxycarboxylic acid (e.g., SnCl2 and gentisic acid) or an alcohol and lipophilic cations (e.g., alcoholic tetrabutylammonium bromide solution).
Then, the thus produced stent can still be sealed with a polymer. As a polymer, e.g., a polyacrylate is suitable.
All stents can also be coated with two or more different isotopes. In particular, it is possible to apply short-lived and long-lived isotopes together on a stent (for example, 55Co with 55Fe or 99Mo with 57Co).
With the described process, it is possible to produce radioactive stents that contain on the surface at least one radioisotope of elements Ag, Au, Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, Pb, Pd, Pm, Pt, Re, Rh, Ru, Sc, Sm, Tb, Tc or Y.
The invention therefore relates to such stents, as well as the processes for their production. The operations that are necessary for implementing the above processes that are described in principle are known to one skilled in the art. Special embodiments are described in detail in the examples.
The stents according to the invention achieve the above-described object. Stents can be radiolabled easily by the disclosed processes and metered precisely. The stents according to the invention are readily physiologically compatible. As it was possible to show in the animal model, the restenosis is significantly inhibited after balloon denudation by implantation of the stent according to the invention.
The special advantage of the stent according to the invention is that the physician can select on the spot a (non-radioactive) stent according to his needs and can then activate the selected stent by the described process. The few substances and solutions that are required for this purpose can be supplied prepared accordingly, so that the corresponding physician need only immerse the uncoated stent in the individual solutions in the specific sequence. The invention thus also relates to those substances, solutions and preparations (kits) that are prepared for the processes according to the invention.
Embodiments